The field of the present invention relates to the delivery of energy impulses (and/or fields) to bodily tissues for therapeutic purposes. The invention relates more specifically to devices and methods for treating conditions associated with stroke and/or transient ischemic attacks. The energy impulses (and/or fields) that are used to treat those conditions comprise electrical and/or electromagnetic energy, delivered non-invasively to the patient.
The use of electrical stimulation for treatment of medical conditions is well known. For example, electrical stimulation of the brain with implanted electrodes (deep brain stimulation) has been approved for use in the treatment of various conditions, including pain and movement disorders such as essential tremor and Parkinson's disease [Joel S. PERLMUTTER and Jonathan W. Mink. Deep brain stimulation. Annu. Rev. Neurosci 29 (2006):229-257].
Another application of electrical stimulation of nerves is the treatment of radiating pain in the lower extremities by stimulating the sacral nerve roots at the bottom of the spinal cord [Paul F. WHITE, Shitong Li and Jen W. Chiu. Electroanalgesia: Its Role in Acute and Chronic Pain Management. Anesth Analg 92 (2001):505-513; U.S. Pat. No. 6,871,099, entitled Fully implantable microstimulator for spinal cord stimulation as a therapy for chronic pain, to WHITEHURST, et al].
Many other forms of nerve stimulation exist [HATZIS A, Stranjalis G, Megapanos C, Sdrolias P G, Panourias I G, Sakas D E. The current range of neuromodulatory devices and related technologies. Acta Neurochir Suppl 97(Pt 1, 2007):21-29]. The type of electrical stimulation that is most relevant to the present invention is vagus nerve stimulation (VNS, also known as vagal nerve stimulation). It was developed initially for the treatment of partial onset epilepsy and was subsequently developed for the treatment of depression and other disorders. The left vagus nerve is ordinarily stimulated at a location within the neck by first implanting an electrode about the vagus nerve during open neck surgery and by then connecting the electrode to an electrical stimulator circuit (a pulse generator). The pulse generator is ordinarily implanted subcutaneously within a pocket that is created at some distance from the electrode, which is usually in the left infraclavicular region of the chest. A lead is then tunneled subcutaneously to connect the electrode assembly and pulse generator. The patient's stimulation protocol is then programmed using a device (a programmer) that communicates with the pulse generator, with the objective of selecting electrical stimulation parameters that best treat the patient's condition (pulse frequency, stimulation amplitude, pulse width, etc.) [Patent numbers U.S. Pat. No. 4,702,254 entitled Neurocybernetic prosthesis, to ZABARA; U.S. Pat. No. 6,341,236 entitled Vagal nerve stimulation techniques for treatment of epileptic seizures, to OSORIO et al; U.S. Pat. No. 5,299,569 entitled Treatment of neuropsychiatric disorders by nerve stimulation, to WERNICKE et al; G. C. ALBERT, C. M. Cook, F. S. Prato, A. W. Thomas. Deep brain stimulation, vagal nerve stimulation and transcranial stimulation: An overview of stimulation parameters and neurotransmitter release. Neuroscience and Biobehavioral Reviews 33 (2009):1042-1060; GROVES D A, Brown V J. Vagal nerve stimulation: a review of its applications and potential mechanisms that mediate its clinical effects. Neurosci Biobehav Rev 29 (2005):493-500; Reese TERRY, Jr. Vagus nerve stimulation: a proven therapy for treatment of epilepsy strives to improve efficacy and expand applications. Conf Proc IEEE Eng Med Biol Soc. 2009; 2009:4631-4634; Timothy B. MAPSTONE. Vagus nerve stimulation: current concepts. Neurosurg Focus 25 (3, 2008):E9, pp. 1-4; ANDREWS, R. J. Neuromodulation. I. Techniques-deep brain stimulation, vagus nerve stimulation, and transcranial magnetic stimulation. Ann. N.Y. Acad. Sci. 993(2003):1-13; LABINER, D. M., Ahern, G. L. Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings. Acta. Neurol. Scand. 115(2007):23-33; AMAR, A. P., Levy, M. L., Liu, C. Y., Apuzzo, M. L. J. Vagus nerve stimulation. Proceedings of the IEEE 96(7, 2008):1142-1151; CLANCY J A, Deuchars S A, Deuchars J. The wonders of the Wanderer. Exp Physiol 98(1, 2013):38-45].
In the present invention, electrical and/or magnetic stimulation of a vagus nerve is used to avert, treat or manage stroke and/or transient ischemic attacks. A stroke is the acute loss of brain function due to loss of normal blood supply to the brain or brainstem, spinal cord, or retina. This can be due to the lack of blood flow (ischemia) caused by blockage of a blood vessel due to thrombosis or arterial embolism. Stroke may also be due to a hemorrhage. A thrombotic stroke occurs when a blood clot (thrombus) forms in one of the brain's arteries, which may be formed in the vicinity of fatty deposits (plaque) that build up in the artery to cause reduced blood flow (atherosclerosis). Less commonly, the thrombus may form at the site of a vasospasm of a migraine sufferer. A thrombus can block a large brain artery (causing widespread brain damage) or a small artery, the latter resulting in a so-called lacunar stroke. An embolic stroke occurs when a blood clot or other debris (embolus) forms outside brain, for example in an atrium of the patient's heart, and is transported through the bloodstream to lodge in an artery of the brain. About half to two-thirds of all strokes are thrombotic strokes.
Ischemic stroke occurs in 87% of stroke patients and may be either symptomatic or silent. Symptomatic ischemic strokes are manifest by clinical signs of focal or global cerebral, spinal, or retinal dysfunction caused by death of neural tissue (central nervous system infarction). A silent stroke is a documented central nervous system infarction (tissue death due to lack of oxygen) that was asymptomatic. Symptomatic ischemic strokes are usually treated with thrombolytic agents (“clot busters”), preferably within three hours of the onset of the stroke. In contrast, hemorrhagic strokes occur in 13% of stroke patients, who may be treated by neurosurgery. Hemorrhagic strokes include bleeding within the brain (intracerebral hemorrhage) and bleeding between the inner and outer layers of the tissue covering the brain (subarachnoid hemorrhage).
A transient ischemic attack (TIA) is also caused by ischemia in the brain, spinal cord or retina. TIAs share the same underlying etiology as ischemic strokes and produce the same symptoms, such as contralateral paralysis, sudden weakness or numbness, dimming or loss of vision, aphasia, slurred speech and mental confusion. Unlike a stroke, the symptoms of a TIA can resolve typically within a day, whereas the symptoms from a stroke can persist due to death of neural tissue (acute infarction). Thus, a transient ischemic attack may be defined as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction [EASTON JD, Saver J L, Albers G W, et al. Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council et al. Stroke 40(6, 2009):2276-2293; PRABHAKARAN S. Reversible brain ischemia: lessons from transient ischemic attack. Curr Opin Neurol 20(1, 2007):65-70].
Stroke accounts for approximately 9.7% of all deaths worldwide. It is the third-leading cause of death in the United States, with more than 140,000 people dying of stroke each year. Some 795,000 individuals suffer a stroke annually in the U.S. (269 per 100,000 population), with 600,000 of these strokes representing first-time attacks. Stroke also causes a substantial medical burden for those individuals who survive a stroke. Overall case-fatality within 1 month of stroke onset is about 23%, but is higher for intracerebral hemorrhage (42%) and subarachnoid hemorrhage (32%) than for ischemic stroke (16%). Among all nonpediatric populations, stroke is the fourth-leading cause of lost disability-adjusted life-years, behind only to HIV/AIDS, unipolar depressive disorders, and ischemic heart disease. The total cost of stroke to the United States is estimated at $43 billion per year, consisting of direct costs of medical care and therapy at $28 billion per year and indirect costs from lost productivity and other factors at $15 million per year [Debraj MUKHERJEE and Chirag G. Patil. Epidemiology and the Global Burden of Stroke. World Neurosurg 76(6 Suppl, 2011):S85-S90; FEIGIN V L, Lawes C M, Bennett D A, Anderson C S. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2(1, 2003):43-53].
The estimated annual number of TIAs in the U.S. is about 200 to 500 thousand, although the number is difficult to estimate because TIAs may be under-reported, considering that they typically last less than an hour. It is not well known by the general public that a TIA is a medical emergency requiring prompt medical attention. Approximately 10% of strokes are preceded by one or more TIAs. An estimated one-third of all TIAs are followed by a stroke within five years [JOHNSTON SC. Transient ischemic attack. N Engl J Med. 347 (2002):1687-1692].
The goal of diagnosis of a TIA is to identify the cause of the TIA and to recommend treatment accordingly. With a carotid artery TIA, symptoms and signs are related to the ipsilateral cerebral hemisphere and/or retina. In amaurosis fugax, cholesterol from ruptured atherosclerotic plaques in the common or internal carotid artery or other types of emboli transiently occludes flow to the retinal artery, causing a sudden onset of monocular blindness. In a certebrobasilar artery TIA, symptoms and signs are related to the posterior cerebral circulation and may affect vision and central nervous system function. A computed tomography scan (CT scan) or a magnetic resonance imaging (MRI) scan is usually the first imaging test for a TIA, followed by carotid ultrasonography. If carotid stenosis is identified, cerebral arteriography may be done. Treatment is aimed at preventing further TIAs and especially at preventing a stroke. Aspirin or another antiplatelet drug is often chosen for drug therapy. Treatment with a statin is recommended for most people after atherothromboembolic TIA. A timely endarterectomy for severe carotid stenosis is likely to prevent future TIAs [JOHNSTON S C, Nguyen-Huynh M N, Schwarz M E, et al. National Stroke Association guidelines for the management of transient ischemic attacks. Ann Neurol 60(3, 2006):301-313; JOHNSTON SC, Rothwell P M, Nguyen-Huynh M N, Giles M F, Elkins J S, Bernstein A L, Sidney S. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 369(9558, 2007):283-292].
Strokes and TIAs have similar risk factors, i.e. factors that increase the likelihood of having a stroke and/or TIA. One of the most significant of them is advancing age, such that the average age of patients affected by stroke is 70 years in men and 75 years in women. Nevertheless, strokes occur in a significant number of infants and children as well, the epidemiology of which is complicated by associated head injuries, infections, migraine headaches, hereditary disorders, and cerebrovascular dysfunction in general [ROACH E S, Golomb M R, Adams R, et al. Management of stroke in infants and children: a scientific statement from a Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young. Stroke 39(9, 2008):2644-2691].
In addition to age, the following are considered to be primary established risk factors for stroke in adults: current smoking, diabetes mellitus, systolic blood pressure, antihypertensive therapy, prior coronary heart disease, left ventricular hypertrophy, and race. However, many other risk factors may be predictive as well, such as body mass index, waist:hip ratio, HDL cholesterol, albumin, von Willebrand factor, alcohol consumption, intima-media thickness, peripheral arterial disease, infection and inflammation, recreational drugs and medications, mental stress, perturbations in systemic metabolism, acute increases in blood pressure, changes in blood coagulation, migraine headache, atrial fibrillation, and carotid stenosis [CHAMBLESS L E, Heiss G, Shahar E, Earp M J, Toole J. Prediction of ischemic stroke risk in the Atherosclerosis Risk in Communities Study. Am J Epidemiol 160(3, 2004):259-269; MacCLELLAN L R, Giles W, Cole J, Wozniak M, Stern B, Mitchell BD, Kittner S J. Probable migraine with visual aura and risk of ischemic stroke: the stroke prevention in young women study. Stroke 38(9, 2007):2438-2445; ELKIND MS. Why now? Moving from stroke risk factors to stroke triggers. Curr Opin Neurol 20(1, 2007):51-57].
Traditional risk assessment using variables such as the ones described in the previous paragraph treats the occurrence of stroke or a transient ischemic attack as a random event, the probability of which is a function of the risk-factor status of the patient. According to that point of view, one prevents strokes in a probabilistic sense by taking steps to develop more favorable risk factor values (e.g., diet change, smoking cessation, control diabetes or blood pressure with medications and/or lifestyle changes, or undergo a carotid endarterectomy or carotid stenting for patients with symptomatic carotid stenosis) [JOHNSEN SP, Overvad K, Stripp C, Tjønneland A, Husted SE, Sørensen HT. Intake of fruit and vegetables and the risk of ischemic stroke in a cohort of Danish men and women. Am J Clin Nutr 78(1, 2003):57-64]. Family history of stroke is also an independent risk factor, suggesting the existence of genetic factors that may interact with environmental factors [Ahamed HASSAN and Hugh S. Markus. Genetics and ischaemic stroke. Brain 123(2000):1784-1812; patent application US20120021989, entitled Genetic markers for risk management of atrial fibrillation and stroke, to HOLM et al.]. Although genetic risk factors, which cannot be changed, may also contribute to the risk of stroke, knowledge of those factors may motivate the patient to address other risk factors.
In a number of commonly assigned, co-pending applications, Applicant disclosed the use of noninvasive vagus nerve stimulation to treat or avert some of conditions that may put the patient at risk for suffering a stroke, particularly atrial fibrillation and migraine headache [US20130131746, entitled Non-invasive vagus nerve stimulation devices and methods to treat or avert atrial fibrillation, to SIMON et al.; US20110276107, entitled Electrical and magnetic stimulators used to treat migraine/sinus headache, rhinitis, sinusitis, rhinosinusitis, and comorbid disorders, to SIMON et al]. Similarly, risk factors that promote the occurrence of stroke will secondarily promote the risk for vascular dementia, which may be caused by multiple mini-strokes [NYENHUIS D L, Gorelick P B. Vascular dementia: a contemporary review of epidemiology, diagnosis, prevention, and treatment. J Am Geriatr Soc 46(11, 1988):1437-1448; WANG J, Zhang H Y, Tang X C. Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment. Acta Pharmacol Sin 30(7, 2009):879-888]. In a commonly assigned, co-pending application, Applicant disclosed the use of noninvasive vagus nerve stimulation to treat or avert dementia, so the present application extends that disclosure [US 20130066392, entitled Non-invasive magnetic or electrical nerve stimulation to treat or prevent dementia, to SIMON et al.] These applications are hereby incorporated by reference.
In another co-pending, commonly assigned application, US20130066395, entitled Nerve stimulation methods for averting imminent onset or episode of a disease, to SIMON et al., Applicant disclosed a different, novel approach to preventing strokes, in which one endeavors to forecast the actual onset of a stroke in an individual, seconds to minutes before the event, and then take prompt prophylactic countermeasures to avert, limit or ameliorate the stroke or TIA. The present application extends that disclosure. Such an approach would be particularly appropriate for individuals who have had a recent TIA and are likely to suffer a stroke in the next few days [JOHNSTON SC, Rothwell P M, Nguyen-Huynh M N, Giles M F, Elkins J S, Bernstein A L, Sidney S. Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 369(9558,2007):283-292].
A stroke causes an infarct, which comprises irreversibly dead or dying neuronal tissue that has been deprived of oxygen. The infarct is surrounded by a penumbra of ischemic tissue, which is salvagable with prompt restoration of oxygen through blood perfusion. Therefore, prompt diagnosis and treatment of the stroke patient is essential in order to save as much of the penumbra tissue as possible, thereby saving the neuronal functions that are performed by that salvagable tissue. Ischemic stroke is generally painless, and the patient usually remains conscious during the diagnosis. Neurological symptoms that are exhibited by the patient upon interrogation and examination are used to make a preliminary evaluation as to whether a stroke has occurred.
During the evaluation, the clinician will attempt to determine the mechanism of the stroke (if any), classifying it as having an indeterminate pathogenesis prior to imaging, an infarct, or a hemorrhage. The clinician will also attempt to determine the blood vessels that are involved, classifying the stroke as a total anterior circulation stroke, a lacunar stroke, a partial anterior circulation stroke, or a posterior circulation stroke. For example, the middle cerebral artery is most commonly affected with the arm more severely affected than the leg. With anterior cerebral artery stroke, the leg is more affected than the arm. Posterior cerebral strokes result in homomynous hemianopsia. Basilar artery strokes are frequently associated with vertigo, diplopia, dysarthria or Horner syndrome, and hemiparesis is not a feature. Cerebral venous sinus thrombosis presents with symptoms and signs of cerebral vascular disease with less discrete evidence of focal lesions. However, the accurate determination of stroke subtype eventually requires neuroimaging to distinguish ischemic from hemorrhagic stroke [STAM J. Thrombosis of the cerebral veins and sinuses. N Engl J Med 352 (2005):1791-1798; THALER D E, Frosch M P. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 16-2002. A 41-year-old woman with global headache and an intracranial mass. N Engl J Med 346(21, 2002):1651-1658].
The diagnosis would also attempt to rule out conditions that mimic stroke, e.g., seizures, hypoglycemia, migraine with aura, hypertensive encephalopathy, Wernicke's encephalopathy, CNS abscess, CNS tumor, or drug toxicity [Goldstein L B, Simel DL. Is this patient having a stroke? JAMA 293 (2005):2391-2402; JAUCH E C, Saver J L, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 44(3, 2013):870-894].
Several testing instruments are commonly used to assess stroke severity as part of the neurological examination of a suspected stroke patient. One such instrument is the NIH Stroke Scale, which involves quantitative assessment of the patient's consciousness, eye movements, visual fields, facial palsy, arm movement, leg movement, coordination of muscle movement, tactile sensory loss, speech comprehension, speech articulation, and attention to simultaneous bilateral stimulation [MEYER BC, Lyden P D. The modified National Institutes of Health Stroke Scale: its time has come. Int J Stroke 4(4, 2009):267-273].
Diagnostic tests are also performed in order to rule out other possible diagnoses and aid in treatment selection, comprising: blood glucose, oxygen saturation, serum electrolytes/renal function tests, complete blood count, including platelet count, markers of cardiac ischemia, prothrombin time/INR, activated partial thromboplastin time, and ECG. Brain imaging, using noncontrast brain CT or brain MRI, then provides invaluable information affecting the treatment decision, including the size, location, and vascular distribution of the infarction, the presence of bleeding, severity of ischemic stroke, and/or presence of large-vessel occlusion. Diffusion-weighted MRI imaging has emerged as the most sensitive and specific technique for imaging an acute infarct. The imaging is preferably performed within 30 minutes of the patient's arrival in an emergency room. Imaging tools are available for measuring the tissue size, location, and topography of the stroke [KENNEDY D N, Haselgrove C, Makris N, Goldin D M, Lev M H, Caplan D, Caviness V S. WebParc: a tool for analysis of the topography and volume of stroke from MRI. Med Biol Eng Comput 48(3, 2010):215-228]. However, such imaging may produce a false negative if it is performed too soon, so measurement of the patient's EEG may also be performed as a companion to the imaging, or in lieu of the imaging if CT or MRI imagers are not available. The information from imaging and EEG are complementary—imaging is predominantly anatomic and static, whereas EEG is predominantly physiologic and dynamic. [JORDAN KG. Emergency EEG and continuous EEG monitoring in acute ischemic stroke. J Clin Neurophysiol 21(5, 2004):341-352; FERREE T C, Hwa R C. Electrophysiological measures of acute cerebral ischaemia. Phys Med Biol 50(17, 2005):3927-3939].
General supportive care and monitoring is then initiated in conjunction with the stroke therapy that is selected. The care and monitoring involves the measurement of oxygen saturation and provision of supplemental oxygen as required; measurement of body temperature and possible induction of hypothermia for purposes of neuroprotection; cardiac monitoring to prevent arrhythmias; measurement of blood pressure and possible manipulation of the pressure to maintain some (but not excessive) cerebral perfusion; correction of hypovolemia with intravenous normal saline; and an attempt to achieve normoglycemia if blood glucose levels are abnormal.
It is impossible to know whether stroke symptoms are due to ischemia or hemorrhage based on clinical characteristics alone. Vomiting, systolic blood pressure greater than 220 mm Hg, severe headache, coma or decreased level of consciousness, and progression over minutes or hours all suggest intracerebral hemorrhage (ICH), although none of these findings are specific. Therefore, neuroimaging is mandatory to make the diagnosis. For patients with a hemorrhage, surgical treatment may be indicated. Patients with cerebellar hemorrhage who are deteriorating neurologically or who have brainstem compression and/or hydrocephalus from ventricular obstruction should undergo surgical removal of the hemorrhage as soon as possible. For patients presenting with lobar clots >30 mL and within 1 cm of the surface, evacuation of supratentorial ICH by standard craniotomy might be considered [MORGENSTERN L B, Hemphill J C 3rd, Anderson C, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 41(9, 2010):2108-2129]. The clinical presentation of an aneurysmal subarachnoid hemorrhage (aSAH) is very distinctive, namely, a headache characterized as being extremely sudden and immediately reaching maximal intensity (thunderclap headache). Surgical clipping or endovascular coiling of the ruptured aneurysm should be performed as early as feasible in the majority of patients to reduce the rate of rebleeding after aSAH [CONNOLLY E S Jr, Rabinstein A A, Carhuapoma J R, et al. Guidelines for the management of aneurysmal subarachnoid hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 43(6, 2012):1711-1737].
Intravenous fibrinolytic (clot dissolving) therapy for acute stroke is currently the primary treatment for ischemic stroke, using intravenous recombinant tissue plasminogen activator (rtPA) at 0.9 mg/kg with a maximum dose of 90 mg, over 60 minutes, with 10% of the dose given as a bolus over 1 minute. The major risk of intravenous rtPA treatment is symptomatic intracranial hemorrhage (sICH). The fibrinolytic therapy is preferably initiated within three hours of the stroke onset, and within one hour after arrival in the emergency room, but the therapy may be useful at up to 4.5 hours after onset of the stroke.
If intravenous fibrinolytic treatment is contraindicated in a patient, or if it does not produce the desired results, other treatment options are available. Endovascular treatment of ischemic stroke has increased substantially over the past decade to include: (1) intra-arterial fibrinolysis, possibly in conjunction with intravenous fibrinolysis; (2) mechanical clot retrieval through mechanical embolectomy using micro-guidewires, micro-snares, retrievers and aspirators, such as the MERCI L5 device (Concentric Medical, Inc, Mountain View, Calif.) and the Penumbra System (Penumbra, Inc, Alameda, Calif.); and (3) acute angioplasty and stenting, e.g., using the TREVO Retriever (Concentric Medical, Inc, Mountain View, Calif.).
The use of thrombin inhibitors and certain anticoagulation therapy (heparin and the like) is not currently recommended. However, oral administration of the antiplatelet agent aspirin (initial dose is 325 mg) within 24 to 48 hours after stroke onset is recommended for treatment of most patients.
Neuroprotective treatment of a stroke patient may also be attempted. Neuroprotection refers to using a therapy that directly affects the brain tissue to salvage or delay the infarction of the still-viable ischemic penumbra, rather than reperfusing the tissue. Neuroprotective strategies include antagonizing the effects of excitatory amino acids, such as glutamate, transmembrane fluxes of calcium, intracellular activation of proteases, apoptosis, free radical damage, inflammation, and membrane damage. More than a thousand neuroprotective therapies have been proposed [O'COLLINS V E, Macleod M R, Donnan G A, Horky L L, van der Worp B H, Howells D W. 1,026 Experimental treatments in acute stroke. Ann Neurol 59 (2006):467-477; GINSBERG MD. Neuroprotection for ischemic stroke: past, present and future. Neuropharmacology 55 (2008):363-389; KIDWELL C S, Liebeskind D S, Starkman S, Saver J L. Trends in acute ischemic stroke trials through the 20th century. Stroke 32 (2001):1349-1359]. These include the use of drugs that limit the cellular effects of acute ischemia or reperfusion (nimodipine, lubeluzole, clomethiazole, NXY-059, tirilazad, citicoline, enlimomab, cerebrolysin, statins, erythropoietin, magnesium, and even the combination of caffeine and alcohol) [PIRIYAWAT P, Labiche L A, Burgin W S, Aronowski J A, Grotta JC. Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke. Stroke 34 (2003):1242-1245].
Another treatment is the use of hypothermia, which has been shown to be neuroprotective in experimental and focal hypoxic brain injury models. An older neuroprotective strategy is the use of hyperbaric oxygen, but clinical data concerning its use are inconclusive, and some data imply that the intervention may be harmful. A relatively new neuroprotective treatment is the application of a near-infrared laser light to the shaved skull to selectively deliver energy to mitochondria in the damaged region [YIP S, Zivin J. Laser therapy in acute stroke treatment. Int J Stroke 3 (2008):88-91].
Electrical stimulation of the vagus nerve has also been investigated as a neuroprotective treatment for stroke [MASADA T, Itano T, Fujisawa M, Miyamoto O, Tokuda M, Matsui H, Nagao S, Hatase O. Protective effect of vagus nerve stimulation on forebrain ischaemia in gerbil hippocampus. Neuroreport 7(2, 1996):446-448]. In experiments by MIYAMOTO et al, the left vagus nerve was exposed at the cervical level and attached to electrodes. Transient global ischemia was induced for 5 minutes by occlusion of the bilateral common carotid arteries. The vagus nerve was stimulated during ischemia using an electrical stimulator, with a strength of 0.4 mA, frequency of 40 Hz and duration of 1 ms. The stimulation rescued approximately 50% of the hippocampal neurons from the ischemic insult [MIYAMOTO O, Pang J, Sumitani K, Negi T, Hayashida Y, Itano T. Mechanisms of the anti-ischemic effect of vagus nerve stimulation in the gerbil hippocampus. Neuroreport 14(15, 2003):1971-1974].
In experiments by HIRAKI et al, the right vagus nerve of a rat was stimulated, starting 30 minutes after proximal middle cerebral artery occlusion, consisting of 30-second pulse trains (20 Hz) delivered to the animal's right vagus nerve every 5 minutes for a total period of 60 minutes. Stimulation of the vagus nerve was found to reduce the infarct size by over 50% and provide neuroprotection for at least 3 weeks [HIRAKI T, Baker W, Greenberg J H. Effect of vagus nerve stimulation during transient focal cerebral ischemia on chronic outcome in rats. J Neurosci Res 90(4, 2012):887-894].
In experiments performed by SUN et al, stimulating electrodes were implanted on the cervical part of the right vagus nerve, and electrical stimulation was initiated 30 minutes after the induction of ischemia and delivered for 30 seconds every 5 minutes for 1 hour. The pulse trains consisted of 0.5 mA square pulses with width 0.3 milliseconds and repetition rate of 20 Hz. Vagus nerve stimulation resulted in a 56.3% decrease in total infarct volume in transient middle cerebral artery occlusion and a 38.4% decrease in permanent middle cerebral artery occlusion [SUN Z, Baker W, Hiraki T, Greenberg J H. The effect of right vagus nerve stimulation on focal cerebral ischemia: an experimental study in the rat. Brain Stimul 5(1, 2012):1-10].
AI and colleagues implanted stimulating electrodes on the cervical part of the right vagus nerve. Electrical stimulation was initiated 30 minutes after the induction of ischemia, and delivered for 30 seconds at every 30 minutes for 3 hours in experimental group 1, and at every 5 minutes for 1 hour in experimental group 2. Square pulses were delivered at a constant current of 0.5 mA with a 30 second train of 0.5 ms pulses delivered at 20 Hz. In both cases, the vagal nerve stimulation reduced infarct size by approximately half [AY I, Lu J, Ay H, Gregory Sorensen A. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia. Neurosci Lett 459(3, 2009):147-151]. In a follow-up investigation, AI and colleagues showed that stimulation of vagus nerve exerts its infarct-reducing effect in the contralateral hemisphere, as well as the ipsilateral hemisphere, such that unilateral vagus nerve stimulation leads to alterations in both hemispheres. The protective mechanism was found not to involve augmenting of cerebral blood flow under ischemic conditions. The authors noted that several potential mechanisms for the observed benefit are: suppression of increased neuronal excitability, reduction of cytokine overproduction and inflammation, and activation of brain regions that are known to elicit neuroprotection upon activation [AY I, Sorensen A G, Ay H. Vagus nerve stimulation reduces infarct size in rat focal cerebral ischemia: an unlikely role for cerebral blood flow. Brain Res 1392 (2011):110-115].
In these reports, AI et al note that the clinical relevance of such findings is limited because the stimulation methods are invasive. Other investigators teach against performing even a noninvasive vagus nerve stimulation at the neck as a protection against neuroinflammation. Thus, in patent application US20080249439, entitled Treatment of inflammation by non-invasive stimulation, to TRACEY et al., it is disclosed that: “An example of such undesirable manner/location is cervical massage of the vagus nerve, which is performed in a location adjacent to the carotid artery and/or carotid body (an organ responsible for monitoring arterial blood pressure). Although non-invasive stimulation at this location can be effective for treating an inflammatory disorder, such stimulation may raise the risk of stroke. Accordingly, the non-invasive stimulation may be understood to mean excluding such regions.”
In the above-mentioned experiments, vagus nerve stimulation was the only treatment for acutely treating the stroke. But in patent application US 20100004717, entitled Timing control for paired plasticity, to KILGARD et al, it is noted that anti-coagulants could be paired with vagus nerve stimulation to act as clot busters during an acute stroke. Some of the above-mentioned investigations attempted to elucidate the mechanism by which vagus nerve stimulation could produce its neuroprotective effect in stroke patients. Related investigations have attempted to elucidate the mechanisms by which vagus nerve stimulation could produce a neuroprotective effect on traumatic brain injury patients, rather than stroke patients [NEESE S L, Sherill L K, Tan A A, Roosevelt R W, Browning R A, Smith D C, Duke A, Clough R W. Vagus nerve stimulation may protect GABAergic neurons following traumatic brain injury in rats: An immunocytochemical study. Brain Res 1128(1, 2007):157-163; BANSAL V, Ryu S Y, Lopez N, Allexan S, Krzyzaniak M, Eliceiri B, Baird A, Coimbra R. Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury. Inflammation 35(1, 2012):214-220].
Yet other potential neuroprotective mechanisms have been discussed in connection with experiments that involved the vagus nerve in stroke patients, but not its electrical stimulation [OTTANI A, Giuliani D, Mioni C, Galantucci M, Minutoli L, Bitto A, Altavilla D, Zaffe D, Botticelli A R, Squadrito F, Guarini S. Vagus nerve mediates the protective effects of melanocortins against cerebral and systemic damage after ischemic stroke. J Cereb Blood Flow Metab 29(3, 2009):512-523; MRAVEC B. The role of the vagus nerve in stroke. Auton Neurosci 158(1-2, 2010):8-12; CHEYUO C, Jacob A, Wu R, Zhou M, Coppa G F, Wang P. The parasympathetic nervous system in the quest for stroke therapeutics. J Cereb Blood Flow Metab 31(5, 2011):1187-1195].
Once the thrombosis, arterial embolism, or hemorrhage has been eliminated and the full extent of tissue damage within the patient's brain has developed, the medically stable patient then undergoes rehabilitation therapy with the objective of recovering function that was lost as a result of the stroke. Speech therapy is appropriate for stroke patients with aphasia, or with dysarthria and apraxia of speech. Occupational therapy is used to help the patient relearn activities of daily living such as eating, dressing, and toileting. Much of the rehabilitation is directed to helping the patient regain motor skills, not only involving hands, arms and legs, but also involving muscles such as those used to swallow [John YOUNG, Anne Forster. Rehabilitation after stroke. BMJ 334 (2007):86-90; BATES B, Choi J Y, Duncan P W, Glasberg J J, et al. Veterans Affairs/Department of Defense Clinical Practice Guideline for the Management of Adult Stroke Rehabilitation Care: executive summary. Stroke 36(9, 2005):2049-2056; RODIN M, Saliba D, Brummel-Smith K et al. Guidelines abstracted from the Department of Veterans Affairs/Department of Defense clinical practice guideline for the management of stroke rehabilitation. J Am Geriatr Soc; 54(1, 2006):158-162; KOLLEN B J, Lennon S, Lyons B, Wheatley-Smith L, Scheper M, Buurke J H, Halfens J, Geurts A C, Kwakkel G. The effectiveness of the Bobath concept in stroke rehabilitation: what is the evidence? Stroke 40(4, 2009):e89-e97; Naoyuki TAKEUCHI and Shin-Ichi Izumi. Rehabilitation with poststroke motor recovery: a review with a focus on neural plasticity. Stroke Research and Treatment Volume 2013, Article ID 128641, pp. 1-13].
Magnetic stimulation is one treatment that has been used to help the patient recover motor skills. However, such magnetic stimulation is applied to the patient's cranium, not to the vagus nerve in the patient's neck, and it resembles the use of transcranial direct current stimulation in that regard [BOLOGNINI N, Pascual-Leone A, Fregni F. Using non-invasive brain stimulation to augment motor training-induced plasticity. J Neuroeng Rehabil 6 (2009):8, pp. 1-13; TROMPETTO C, Assini A, Buccolieri A, Marchese R, Abbruzzese G. Motor recovery following stroke: a transcranial magnetic stimulation study. Clin Neurophysiol 111(10, 2000):1860-1867; KHEDR E M, Ahmed M A, Fathy N, Rothwell JC. Therapeutic trial of repetitive transcranial magnetic stimulation after acute ischemic stroke. Neurology 65(3, 2005):466-468; Anwen EVANS. Transcrianial magnetic stimulation and stroke: a review. The Magstim Company Ltd, Spring Gardens, Whitland, Carmarthenshire, SA34 0HR, United Kingdom, 2008. pp. 1-29; CORTI M, Patten C, Triggs W. Repetitive transcranial magnetic stimulation of motor cortex after stroke: a focused review. Am J Phys Med Rehabil 91(3, 2012):254-270; HSU W Y, Cheng C H, Liao K K, Lee I H, Lin Y Y. Effects of repetitive transcranial magnetic stimulation on motor functions in patients with stroke: a meta-analysis. Stroke 43(7, 2012):1849-1857].
Complementary and alternative medicine interventions have also been used to treat the symptoms of stroke. In a review of acupuncture treatment beginning up to one month after the stroke, beneficial effects could not be ascertained. The acupuncture treatment points are ordinarily on the scalp and certain places on the body, but not in the vicinity of the vagus nerve on the neck [ZHANG S, Liu M, Asplund K, Li L. Acupuncture for acute stroke. Cochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD003317, pp. 1-37].
Electical stimulation of the patient's vagus nerve has been proposed as a treatment for the recovery of motor skills during stroke rehabilitation. As described by KILGARD and colleagues, the vagus nerve stimulation is applied simultaneously (paired) with patient movements [Patent application US20130041419, entitled Methods, systems, and devices for pairing vagus nerve stimulation with motor therapy in stroke patients, to KILGARD et al.; PORTER B A, Khodaparast N, Fayyaz T, Cheung R J, Ahmed S S, Vrana W A, Rennaker R L 2nd, Kilgard M P. Repeatedly pairing vagus nerve stimulation with a movement reorganizes primary motor cortex. Cereb Cortex 22(10, 2012):2365-2374].
Spatial neglect is characterized by a failure to attend to, look at, and respond to stimuli (objects, food, people) located on the side of the body opposite to the side affected by the infarct [HEILMAN KM, Valenstein E, Watson RT. Neglect and related disorders. Semin Neurol 20(4, 2000):463-470]. It is apparently due to damage or loss of connections within networks in the brain known as the dorsal and ventral attention networks [CORBETTA M, Kincade M J, Lewis C, Snyder A Z, Sapir A. Neural basis and recovery of spatial attention deficits in spatial neglect. Nat Neurosci 8(11, 2005):1603-1610; CARTER AR, Astafiev S V, Lang C E, Connor L T, Rengachary J, Strube M J, Pope D L, Shulman G L, Corbetta M. Resting interhemispheric functional magnetic resonance imaging connectivity predicts performance after stroke. Ann Neurol 67(3, 2011):365-375; VERDON V, Schwartz S, Lovblad K O, Hauert C A, Vuilleumier P. Neuroanatomy of hemispatial neglect and its functional components: a study using voxel-based lesion-symptom mapping. Brain 133(Pt 3, 2010):880-894].
Current treatment for spatial neglect consists of finding ways to bring the patient's attention toward the inattentive side (usually left), done incrementally, beginning a few degrees past midline [PIERCE SR, Buxbaum LJ. Treatments of unilateral neglect: a review. Arch Phys Med Rehabil 83(2, 2002):256-268; LUAUTE J, Halligan P, Rode G, Rossetti Y, Boisson D. Visuo-spatial neglect: a systematic review of current interventions and their effectiveness. Neurosci Biobehav Rev 30(7, 2006):961-982; BOWEN A, Lincoln NB. Cognitive rehabilitation for spatial neglect following stroke. Cochrane Database Syst Rev (2, 2007):CD003586, pp. 1-46]. Stimulation methods have been used to treat spatial neglect in patients, consisting of galvanic vestibular stimulation, transcranial magnetic stimulation and transcranial direct-current stimulation, but not vagus nerve stimulation, much less noninvasive vagus nerve stimulation [LIM JY, Kang E K, Paik N J. Repetitive transcranial magnetic stimulation to hemispatial neglect in patients after stroke: an open-label pilot study. J Rehabil Med 42(5, 2010):447-452]. All such methods have been concerned with the rehabilitation of a stroke patient with spatial neglect. In contrast, the present invention also discloses limiting the extent of potential spatial neglect by using vagus nerve stimulation before or during the acute phase of the stroke. In that aspect of the invention, the therapy resembles the use of light deprivation to limit attentional deficits in traumatic brain injury patients, wherein the light deprivation limits eventual attentional deficits, but not necessarily sensorimotor deficits [VARGO J M, Grachek R A, Rockswold G L. Light deprivation soon after frontal brain trauma accelerates recovery from attentional deficits and promotes functional normalization of basal ganglia. J Trauma 47(2, 1999):265-272].
To summarize the foregoing background information, stroke and transient ischemic attacks cause major medical and public health problems. Current methods for treating them are only partially successful, either acutely or in the rehabilitative patient. Although animal experiments suggest that treatment of a stroke in its acute phase using vagus nerve stimulation may be neuroprotective, methods used in those experiments are of limited utility because they are invasive.